principles of drug action exam 3 PD AD Flashcards
WHAT IS PARKINSON‘S DISEASE?
Parkinson Disease is a neurodegenerative disorder of the central nervous system (CNS)
Tremor-resting
Rigidity
Akinesia/Bradykinesia
Slowness in initiation and execution of voluntary movements
Posture and gait
Shuffling feet with abnormal fixation of posture (stoop when
standing), equilibrium, and righting reflex
how does dopamine effect PD
In PD, most of the brain cells that produce dopamine that are located in the substantia nigra have undergone neurodegeneration and died, causing a severe shortage of dopamine in the striatum/basal ganglia.
KEY DOPAMINE PATHWAYS
Nigrostriatal system
Nigrostriatal system
Dopamine neurons originating in substantia nigra and terminating in corpus striatum (basal ganglia)
Nigrostriatal Pathway
Deficiency of dopamine associated with MOVEMENT Disruptions
NIGROSTRIATAL PATHWAY AND THE BASALGANGLIA
Group of interconnected forebrain nuclei including:
– Caudate nucleus
– Putamen
– Globus pallidus
– Subthalamic Nucleus
and… closely associated midbrain nuclei:
– Substantia nigra – Thalamus
BASAL GANGLIA CIRCUIT AND EFFECTS OFDA
Direct Pathway - Cortex to striatum (GABAergic cells expressing D1 receptors) to Gpi/SNpr to thalamus to cortex
NOTE: presence of DA stimulates this pathway and promotes movement
Indirect pathway- Cortex to striatum (GABAergic cells expressing D2 receptors) to GPe to STN to GPi/SNpr to thalamus to cortex.
NOTE: Presence of DA inhibits this pathway and also promotes movement;
WHAT CAUSES PARKINSON’S DISEASE?
Genetic factors
Parkin, alpha-synuclein, others
Environmental factors
Many have been identified, including head injuries and exposure to certain toxins and pesticides.
Early Pathology
-Environmental insults may play a primary role in patients with PD onset Late
after age 50.
Neuroleptic-induced Parkinsonism: 7% - 9%.
- Phenothiazines
- Butyrophenones
- Reserpine
PHARMACOTHERAPY OPTIONS FOR PD
ALL available pharmacotherapy options treat symptoms
Restore function and quality but over time they are ineffective
Not effective for dementia and cognitive impairment which occur later in late stages of disease
Dopaminergic agents-attempt to replace dopamine Levodopa (L-DOPA)
[Dopamine agonists]
DA metabolism inhibitors-managing symptoms
Decarboxylase inhibitors Carbidopa
MAO-B inhibitors Selegiline
COMT inhibitors [Entacapone, Tolcapone]
SO WHAT DRUGS DO WE USE TO TREAT PD?
Parkinson disease medicines can help control or improve certain symptoms of the disease, such as trouble moving the body, stiffness, and shaking (called “tremors”)
Currently, no medicines can cure Parkinson disease or keep it from getting worse over time.
LEVODOPA (L-DOPA)
Most effective drug for Parkinsonian symptoms.
Virtually all patients with confirmed PD experience clinically significant benefit.
Sites of Action of Parkinson’s Disease Drugs
Levodopa –aadc–> Dopamine to striatum
AADC
- Requires active transport across the blood-brain barrier
- Requires metabolic conversion to dopamine by dopamine decarboxylase (AADC)
3 neurons include
Substantia Nigra :ACh
In Parkinson’s disease, the dopaminergic neurons in the substantia nigra degenerate
striatum : receives glutamatergic and dopaminergic inputs from different sources. In particular, the subthalamic nucleus (STN) becomes overactive and acts as a brake on the globus pallidus interna (GPi), causing shutdown of motion and rigidity
globud pallidus interna: When the GPi is overstimulated, it has an over-inhibitory effect on the thalamus, which in turn decreases thalamus output and causes tremor (Fig. 3).
L-DOPA PHARMACOKINETICS
L-Dopa is readily absorbed from GI Tract
- Usually large doses must be given due to First Pass Effect since ~1% actually cross Blood Brain Barrier and enters CNS
- Large amount of L-Dopa has to be given since L- Dopa is also metabolized by dopa decarboxylase in liver and periphery to dopamine.
- Rational for the use of Carbidopa, increases the bioavailability to CNS to >10%
- Secreted in urine unchanged or conjugated with glucuronyl sulfate
ADVERSE EFFECTS OF L-DOPA / DOPAMINE (AND DOPAMINE RECEPTOR AGONISTS)
The most common short-term side effects are nausea, headache, feeling dizzy, and feeling sleepy
-Nausea and vomiting (>80% on initiation)
- Dopamine activates emetic centers [Chemoreceptor
- Trigger Zone (CTZ)] in CNS
- Tachycardia, increased contractility, arrhythmias
- Stimulates β1 receptors in heart—>increases HR and force of contraction.
- Orthostatic hypotension (30%)
- Stimulates DA receptors in mesenteric and renal vascular beds–>
vasodilation.
-Behavioral disturbances (hallucinations, paranoia, mania, delusions, confusion)
dopmaine agonist
ergot
Bromocriptine (D2)
Cabergoline (D2)
Pergolide (D1/D2)
non-ergot
Pramipexole (D3/D2)
Ropinirole (D3/D2)
DISTINGUISHING FEATURES ANDADVANTAGES
Directly stimulate dopamine receptors
No metabolic conversion
No absorption delay from competition with dietary amino acids
Longer half-life than levodopa
Can be used as monotherapy or adjunctive
therapy with levodopa and other medications
May delay or reduce motor fluctuations & dyskinesias associated with levodopa therapy
Contraindicated in patients with history of psychosis
whichDopamine Agonists drug
Also used for neuroleptic malignant syndrome…
- See with typical antipsychotics
- Approved for use in Diabetes
Bromocriptine (Parlodel®)
which dopamine agonist drug
voluntarily discontinued in US due to cardiac valve disorders
Pergolide (Permax®)
•Pergolide voluntarily discontinued in US due to cardiac valve disorders
Non-Ergot Derived Dopamine agonists
Ropinirole (Requip®)- ORAL
- Pramipexole (Mirapex®) ORAL
- Rotigotine (Neupro®)-Patch
Apomorphine (Apokyn) injector
ROTIGOTINE (NEUPRO®)
Neupro is a non-ergoline D3/D2/D1 dopamine agonist, which uses a transdermal delivery system for continuous delivery over a 24-hour period.
Neupro was removed due to reports of rotigotine crystals forming in the patches. The formation of rotigotine crystals results in reduced absorption and altered efficacy
-Approved for use in patients with early-stage PD
side effects : Nausea and vomiting, dizziness, somnolence, headache, insomnia, extremity edema (e.g. swollen hands and feet), and application site reactions.
APOMORPHINE (APOKYN®)
-POTENT mixed agonist at D
Treatment of unpredictable, frequent motor fluctuations
Supplied pen injection system
- Dose of Apokyn must be titrated and started in medical office
- SE: nausea, vomiting, hypotension
DOPAMINE AGONISTS: COMMON ADVERSE EFFECTS
Not as effective as L-dopa and most patients will eventually require L-dopa supplementation.
Nausea, vomiting
Dizziness, postural hypotension, lower limb edema
Headache, confusion, hallucinations, paranoia
Drowsiness & somnolence
Dyskinesias
Erythromelalgia; pulmonary & peritoneal fibrosis; pleural effusion & pleural thickening; Raynaud’s phenomena.
ERYTHROMELALGIA & RAYNAUD’S PHENOMENON
Erythromelalgia: Neurovascular peripheral pain disorder in which blood vessels in the lower extremities are episodically blocked, then become hyperemic and inflamed, resulting in severe burning pain and skin redness.
raynaud: Disorder causing discoloration of fingers, toes, and other areas, believed to be the result of vasospasms that decrease blood supply and hypoxia of the affected areas
____ and ___ increase bioavailability of L-DOPA to the CNS
decarboxylase and COMT
CATECHOLAMINE INACTIVATION: ROLE OF DEGRADING ENZYMES
COMT inhibitors block peripheral metabolism of levodopa and increases its bioavailability to the CNS in Parkinson’s disease
CATECHOL-O-METHYL TRANSFERASE(COMT) INHIBITORS
COMT inhibitors are medicines taken with levodopa that help levodopa work longer and better
Utilized primarily to treat people whose levodopa “wears off” before the next dose (motor fluctuations
ENTACAPONE (COMTAN®)
Increases “on time” by ~10%; Greater improvement in patients with the least amount of “on time”
Available as Stalevo combination tablet (L- DOPA; Carbidopa and Entacapone)
Dose adjustments for L-DOPA may be necessary depending on prior therapy
Does not enter the CNS
Side effects: nausea, dyskinesia/hyperkinesia, diarrhea, abdominal pain, urine discoloration.
TOLCAPONE (TASMAR®)
First COMT inhibitor licensed in the U.S.
Reduced LD dosage by 12%, improved motor fluctuations by 14%
“On time” increased >1.5 hrs/day Improvements in QOL measures
Enters CNS, but not the primary action
Side effects: Dizziness, orthostasis,diarrhea,
dyskinesias, confusion
Acute fulminant hepatic necrosis
SELECTIVE MAO-B INHIBITORS
- Selective irreversible inhibitors of MAO-B
- Monotherapy oradjunct
- Adverse effects include nausea, dizziness, abdominal pain, confusion, and exacerbation of L-DOPA side effects
- Tyramine consumption and MAO not as big an issue due to selectivity for MAO-B vs non- or MAO-A selective agents
SELEGILINE (ELDEPRYL®)
Selegiline is an irreversible monoamine oxidase-B (MAO-B) inhibitor (dose-dependent selectivity)
Primarily used as adjunctive therapy with L-DOPA
SELEGILINE (ELDEPRYL VS ZELAPAR)
Eldepryl:
• Metabolized by CYP enzymes to
amphetamines/methamphetamines
• Dosed BID at breakfast and lunch with carbidopa/L-
DOPA
• Can contribute to agitation
Zelapar:
Once daily dosing
ODT that bypasses liver decreases/limits
amphetamine formation
• Faster onset of action, improved bioavailability (80%)
and tolerability
RASAGILINE (AZILECT®)
Newer agent: Rasagiline is a selective irreversible MAO-B inhibitor; can be used as monotherapy early or as add-on later
CYP1A2 substrate
No amphetamine like metabolites, so improved tolerability
On-Off effect: Oscillations in response and sudden changes in mobility from no symptoms to full Parkinsonian symptoms in a matter of minutes
Decreases “off” time for patients on stable doses of carbidopa/levodopa
ANTI-CHOLINERGICS
Dopaminergic Depletion –> Cholinergic Overactivity
Historically the first therapies used for treatment of PD
Effective for mild symptoms (mainly for tremor);
reserved for younger patients; avoid use in elderly patients
Monotherapy or adjunct
Common agents (Start low, go slow): Benztropine (Cogentin®) Trihexyphenidyl (Artane)®
Side effects (anti-SLUD and CNS effects):
Dry mouth, constipation, urinary retention, sedation, blurred vision, and increased intraocular pressure; delirium, confusion, memory impairment, hallucinations, delusions
AMANTADINE (SYMMETREL®)
Antiviral agent; PD benefit found accidentally
- Best for early stage, short term therapy
Side effects — autonomic, psychiatric, livedo reticularis
Exact mechanism unknown but possibly related to:
Enhancing release of stored dopamine
inhibiting presynaptic reuptake of catecholamines
Dopamine receptor agonist
Weak, non-competitive NMDA receptor antagonist
Although not shown to possess anticholinergic activity, it exhibits anticholinergic-like side effects
Dry mouth, urinary retention, and constipation
